PROJECT SUMMARY/ABSTRACT The goal of this research is to characterize the long-term impact of Alzheimer disease (AD) brain pathology on driving behavior and driving cessation among persons with and without preclinical AD. Our findings indicate that the long preclinical stage of AD, as reflected in amyloid imaging and cerebrospinal fluid (CSF) biomarkers among cognitively normal persons, is associated with poorer driving performance on a standardized road test. This research is significant because 36 million licensed drivers are aged 65 years or older, and the number of older adults in the United States is expected to double by 2050, when 1 in 4 drivers will be 65 years or older. Motor vehicle crashes are a leading cause of injury and death in older adults. The ability to identify who will be at most risk of driving decline and to predict when decline will occur will inform early driving safety intervention trials for older adults. Preclinical AD is an important stage during which to plan and implement safety measures in anticipation of changes in driving skills with disease progression. Our Specific Aims will determine how levels of both novel and well-established AD biomarkers and other age- and disease-associated factors are related to driving performance across the course of preclinical AD: (1) To maintain and grow our unique cohort of older adult drivers with and without preclinical AD. (2) To test whether preclinical AD predicts cross-sectional differences and longitudinal changes in naturalistic driving. (3) To identify driving, biomarker, clinical, physical, and behavioral predictors of driving cessation, and to develop predictive models using these variables. To test these Specific Aims, we have assembled a multidisciplinary team with expertise in AD, neuroimaging biomarkers, CSF biomarkers, driving generally, naturalistic driving specifically, cognitive and brain aging, and longitudinal biostatistical methods. We will capitalize on existing infrastructure to follow our current cohort of 180 cognitively normal participants with and without preclinical AD, and add additional participants to create a cohort of 300 individuals. This larger cohort will continue to undergo an annual driving test, as well as utilize a naturalistic driving methodology that will capture their driving behaviors on an everyday basis. The long-term impact of AD brain pathology will be defined in several ways to help understand its impact on driving performance, behavior, and cessation. Additionally, we will create predictive models of driving cessation. Once obtained, this knowledge can be used to create stage-appropriate, personalized, driving-related safety strategies that can be implemented upon diagnosis, and adjusted throughout disease progression.